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The molecular mechanism of EGF receptor activation in pancreatic -cells by thyrotropin-releasing hormone

¹The Center of Stem Cell Biology, Department of Research, Roger Williams Hospital; ²Pediatrics, Women and Infants Hospital; and ³Program in Liberal Medical Education, Brown University, Providence, Rhode Island

Submitted 23 September 2005 ; accepted in final form 6 December 2005

Thyrotropin-releasing hormone (TRH) and its receptor subtype TRH receptor-1 (TRHR1) are found in pancreatic -cells, and it has been shown that TRH might have potential for autocrine/paracrine regulation through the TRHR1 receptor. In this paper, TRHR1 is studied to find whether it can initiate multiple signal transduction pathways to activate the epidermal growth factor (EGF) receptor in pancreatic -cells. By initiating TRHR1 G protein-coupled receptor (GPCR) and dissociated -complex, TRH (200 nM) activates tyrosine residues at Tyr⁸⁴⁵ (a known target for Src) and Tyr¹⁰⁶⁸ in the EGF receptor complex of an immortalized mouse -cell line, TC-6. Through manipulating the activation of Src, PKC, and heparin-binding EGF-like growth factor (HB-EGF), with corresponding individual inhibitors and activators, multiple signal transduction pathways linking TRH to EGF receptors in TC-6 cell line have been revealed. The pathways include the activation of Src kinase and the release of HB-EGF as a consequence of matrix metalloproteinase (MMP)-3 activation. Alternatively, TRH inhibited PKC activity by reducing the EGF receptor serine/threonine phosphorylation, thereby enhancing tyrosine phosphorylation. TRH receptor activation of Src may have a central role in mediating the effects of TRH on the EGF receptor. The activation of the EGF receptor by TRH in multiple circumstances may have important implications for pancreatic -cell biology.

heparin-binding epidermal growth factor-like growth factor; Src; protein kinase C; G protein; signal transduction

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